Personalized auditory-somatosensory stimulation to treat tinnitus

ABSTRACT

Timed stimulation of both somatosensory system and auditory system is controlled, in such a manner, that an individual&#39;s brain activity is altered through spike-timing dependent plasticity, thereby reducing or removing tinnitus.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Application No. 61/800,607,filed Mar. 15, 2013, entitled “Personalized Auditory-SomatosensoryStimulation to Treat Tinnitus” and U.S. Application No. 61/803,062,filed Mar. 18, 2013, entitled “Personalized Auditory-SomatosensoryStimulation to Treat Tinnitus,” both of which are hereby incorporated byreference in their entirety.

GOVERNMENT SPONSORSHIP CLAUSE

This invention was made with government support under DC004825, DC005188and DC000011 awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

BACKGROUND OF THE DISCLOSURE

1. Field of Technology

The present disclosure relates generally to treatment and tinnitus and,more particularly, to the use of a bimodal stimulation, with stimulationof the auditory and somatosensory systems, to treat tinnitus.

2. Background

The background description provided herein is for the purpose ofgenerally presenting the context of the disclosure. Work of thepresently named inventor, to the extent it is described in thisbackground section, as well as aspects of the description that may nototherwise qualify as prior art at the time of filing, are neitherexpressly nor impliedly admitted as prior art against the presentdisclosure.

Tinnitus is the phantom perception of sound experienced in a subject'sear or head, when no actual sound is present. Tinnitus, consideredsubjective phenomenon, can vary in degrees of severity. One commonlyreferred to expression of tinnitus is “ringing in the ears”; but thereare many different forms of tinnitus.

Tinnitus has been linked to somatosensory innervation of the auditorysystem. For example, both tinnitus patients and normal subjects reportthat somatosensory stimuli such as pressure on the face or movement ofthe jaw or neck can elicit or modulate the tinnitus perception. In termsof physiology, converging somatosensory and auditory inputs areintegrated in the dorsal cochlear nucleus (DCN), an auditory brainstemnucleus receiving afferent input from the auditory nerve. It is believedthat somatosensory input to this DCN plays a role in the induction oftonotopically-restricted hyperactivity in the DCN that has beencorrelated with tinnitus.

Unfortunately, present techniques for reducing tinnitus are inadequate.Some techniques, for example, are overly intrusive, requiring deep brainaccess through embedded probes, which makes these techniques undesirablefor widespread use. Some techniques provide temporary relief from thetinnitus using external stimuli but fail to address the underlyingcauses of tinnitus in patients, leaving patient's susceptible to furthertinnitus bouts, and often soon after treatment.

SUMMARY

The disclosure demonstrates stimulus timing dependent plasticity in vivoas a mechanism underlying multisensory integration. The timing rules andtime course of the observed stimulus-timing dependent plasticity closelymimic those of spike-timing dependent plasticity that has beendemonstrated in vitro in the dorsal cochlear nucleus (DCN). Spike-timingdependent plasticity is important for adaptive processing and is amechanism for deemphasizing body-generated signals, such asvocalizations, by suppressing sound-evoked responses that are predictedby activation of somatosensory inputs. By manipulating spike timingdependent plasticity through unique multisensory stimulation, we havedeveloped techniques capable of reducing and removing phantom soundperception or tinnitus, in which cross-modal plasticity is an underlyingmechanism.

The disclosure provides techniques for controllably timed stimulation ofboth the somatosensory system and the auditory system, in such a manner,that an individual's brain activity is altered through spike-timingdependent plasticity, thereby reducing or removing tinnitus. We showthat multisensory neurons in the DCN show long-lasting plasticity ofsound-evoked responses and spontaneous activity when stimulated withcombined somatosensory-auditory stimulation. By varying the intervalsbetween sound and somatosensory stimuli, we show for the first time invivo that this DCN bimodal plasticity is stimulus-timing dependent. Thetiming rules and time courses of the observed stimulus-timing dependentplasticity closely mimic those of spike-timing dependent plasticity thathave been demonstrated in vitro at parallel-fiber synapses onto DCNprincipal cells. Furthermore, the degree of inhibition in neuron firinginfluences whether that neuron has Hebbian or anti-Hebbian timing rules.As demonstrated, anti-Hebbian timing rules reflect adaptive filtering,which in the DCN would result in suppression of sound-evoked responsesthat are predicted by activation of somatosensory inputs, leading to thesuppression of body-generated signals such as self-vocalization.

In an embodiment, a method of treating tinnitus in a subject, includes:generating an audible stimulation signal having a first firing point andfirst firing period; generating a somatosensory stimulation signal tostimulate a somatosensory system of a subject, the somatosensorystimulation signal having a second firing point and second firingperiod; and establishing a timing order and timing difference betweenthe first firing point and the second firing point to reduce thetinnitus, wherein the first firing period and the second firing periodare to be maintained asynchronously to reduce tinnitus so that onset ofthe first firing period does not significantly overlap onset of thesecond firing period.

In another embodiment, a system for treating an auditory condition in asubject, comprises: a processor and a memory; and a bimodal stimulationsystem configured to, generate an audible stimulation signal having afirst firing point and first firing period, stimulus onset, and/orduration, generate a somatosensory stimulation signal to stimulate asomatosensory system of a subject, the somatosensory stimulation signalhaving a second firing point and second firing period, stimulus onset,and/or duration, and establish a timing order and timing differencebetween the first firing point and the second firing point to reduce thetinnitus, wherein the first firing period and the second firing periodare to be maintained asynchronously to reduce tinnitus so that the onsetof the first firing period does not overlap the onset of the secondfiring period.

In yet another embodiment, a computer-readable storage medium havingstored thereon a set of instructions, executable by a processor, fortreating an auditory condition in a subject, the instructions comprises:instructions for generating an audible stimulation signal having a firstfiring point and first firing period, stimulus onset, and/or duration;instructions for generating a somatosensory stimulation signal tostimulate a somatosensory system of a subject, the somatosensorystimulation signal having a second firing point and second firingperiod, stimulus onset, and/or duration; and instructions forestablishing a timing order and timing difference between the firstfiring point and the second firing point to reduce the tinnitus, whereinthe first firing period and the second firing period are to bemaintained asynchronously to reduce tinnitus so that the onset of thefirst firing period does not overlap the onset of the second firingperiod.

In another embodiment, a computer-readable storage medium having storedthereon a set of instructions, executable by a processor, for treatingan auditory condition in the a subject, the instructions comprises:instructions for determining optimal parameter values for an audiblestimulation signal and a somatosensory stimulation signal to alterfiring rates for neurons in the auditory pathway, including but notlimited to dorsal cochlear nucleus, ventral cochlear nucleus, inferiorcolliculus, auditory cortex, and/or other nuclei associated withtinnitus. More generally, the optimal parameter values may be determinedto alter firing rates along any of the auditory and non-auditorypathways involved in the auditory condition (e.g., tinnitus).

In another embodiment, a method, for treating an auditory condition inthe subject, the method comprises: determining optimal parameter valuesfor an audible stimulation signal and a somatosensory stimulation signalto alter firing rates for neurons in the auditory pathway, including butnot limited to dorsal cochlear nucleus, ventral cochlear nucleus,inferior colliculus, auditory cortex, and/or other nuclei associatedwith tinnitus. More generally, the optimal parameter values may bedetermined to alter firing rates along any of the auditory andnon-auditory pathways involved in the auditory condition (e.g.,tinnitus).

In some examples, the method includes increasing firing rates for theneurons in the auditory pathway, including but not limited to dorsalcochlear nucleus, ventral cochlear nucleus, inferior colliculus,auditory cortex, and/or other nuclei associated with tinnitus. Moregenerally, the optimal parameter values may be determined to alterfiring rates along any of the auditory and non-auditory pathwaysinvolved in the auditory condition (e.g., tinnitus).

In some examples, the method includes decreasing firing rates for theneurons in the auditory pathway, including but not limited to dorsalcochlear nucleus, ventral cochlear nucleus, inferior colliculus,auditory cortex, and/or other nuclei associated with tinnitus. Moregenerally, the optimal parameter values may be determined to alterfiring rates along any of the auditory and non-auditory pathwaysinvolved in the auditory condition (e.g., tinnitus).

In another embodiment, a system for treating an auditory condition in asubject, the system comprises: a processor and a memory; and a bimodalstimulation system configured to, determine optimal parameter values foran audible stimulation signal and a somatosensory stimulation signal toalter firing rates for neurons in the dorsal cochlear nucleus, ventralcochlear nucleus, and/or auditory cortex. More generally, the optimalparameter values may be determined to alter firing rates along any ofthe auditory and non-auditory pathways involved in the auditorycondition (e.g., tinnitus).

In yet another embodiment, a method of treatment comprises: identifying,in a bimodal stimulation system, initial parameters for timing andintervals of a bimodal stimulation for a subject by identifyingstimulation parameters that in the subject produce a reduction inobjective measures of neural correlates of tinnitus assessed by any ofan electroencephalography test, auditory brainstem response (ABR) test,or subjective measures of tinnitus perception assessed by any of apsychophysical tinnitus matching test or patient questionnaires.

In another embodiment, a system of treatment comprises: a processor anda memory; and a bimodal stimulation system configured to identifyinitial parameters for timing and intervals of a bimodal stimulation fora subject by identifying stimulation parameters that in a subjectproduce a reduction in objective measures of neural correlates oftinnitus assessed by any of an electroencephalography test, auditorybrainstem response (ABR) test, or subjective measures of tinnitusperception assessed by any of a psychophysical tinnitus matching test orpatient questionnaires.

In another embodiment, a computer-readable storage medium having storedthereon a set of instructions, executable by a processor, for treatingan auditory condition in a subject, the instructions comprises:instructions for identifying initial parameters for timing and intervalsof a bimodal stimulation for a subject by identifying stimulationparameters that in the subject produce a reduction in objective measuresof neural correlates of tinnitus assessed by any of anelectroencephalography test, auditory brainstem response (ABR) test, orsubjective measures of tinnitus perception assessed by any of apsychophysical tinnitus matching test or patient questionnaires.

In some examples, the bimodal stimulation comprises an audiblestimulation signal and a somatosensory stimulation signal.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is an example multisensory stimulation configuration 100 forbimodal stimulation of two different types of synapses.

FIG. 1B illustrates an example protocol 200 for measuring the effect ofbimodal stimulation on neurons, through the use of a bimodal pairingprotocol, having 5 steps, in the illustrated example.

FIG. 1C illustrates five plots of firing rate versus time (a firing ratemap), for each of the steps in FIG. 1B.

FIG. 2A illustrates plots of spike counts versus time for 7 (seven)different bimodal timing values, between a somatosensory stimulation andan auditory stimulation.

FIGS. 2B-2E each illustrate a plot of change in firing rates versus timefor different times after bimodal stimuli (e.g., 5 mins, 15, mins, and25 mins) corresponding to the protocol of FIG. 1B, for Hebbian-like(FIG. 2B), anti-Hebbian-like (FIG. 2C), enhanced (FIG. 2D), andsuppressed (FIG. 2E) measurements.

FIGS. 2F-2I each illustrate a plot of demonstrating the mean single unittiming rules for each group are shown in FIGS. 2B-2E, with correspondingidentifies.

FIG. 3A illustrates a plot of a firing rate mapping, for different timesafter bimodal stimulation, showing maximal enhancement and suppression.

FIG. 3B illustrates a plot of spike rates for different, extendedperiods of time after bimodal stimulation.

FIG. 4 illustrates a plot of change in firing rate versus bimodalinterval to show a population estimate of the stimulus-timing dependenceof bimodal plasticity, in accordance with an example.

FIGS. 5A and 5B illustrate plots of change in firing rate for bimodalstimulation versus unimodal tone stimulation (FIG. 5A) and unimodalsomatosensory stimulation (FIG. 5B), respectively.

FIGS. 6A and 6B illustrate responses of six different neurons to 5p5stimulation with either an inhibitory response (FIG. 6A) or anexcitatory response (FIG. 6B), for Hebbian timing rules.

FIGS. 6C and 6D illustrate responses of six different neurons to 5p5stimulation with either an inhibitory response (FIG. 6C) or anexcitatory response (FIG. 6D), for Anti-Hebbian timing rules.

FIG. 7A illustrates a plot of percentage of neurons that experienceHebbian and anti-Hebbian-like units for types I, I-III, III, and IV,response map classifications.

FIG. 7B illustrates a plot of changes in firing rate versus bimodalinterval for buildup or pauser-buildup units with type I or type IIresponse areas exhibiting Hebbian-like timing rules.

FIG. 7C illustrates a plot of changes in firing rate versus bimodalinterval for buildup or pauser-buildup units with type IV or IV-Tresponse maps exhibited only anti-Hebbian timing rules.

FIG. 8 is a plot of change in firing rate versus change in spontaneousrate and showing a linear regression analysis.

FIG. 9 illustrates multiple plots of noise exposure, gap detectiontesting for tinnitus, auditory brainstem response thresholdmeasurements, and partition of guinea pigs into sham, exposure, andtinnitus regions, in accordance with an example.

FIG. 10A illustrates a schematic of the startle based gap-detectionassay text for tinnitus, illustrated no gap (top row) and gap trials (50ms gap, 50 ms before the startle sound, bottom two rows). Each testincluded background sound (grey bar) with a 10 ms, 115 dB startle pulseembedded (black bar). The guinea pig startles in response to the startlestimulus, with the amplitude of the response shown by the height of eacharrow. In animals without tinnitus, the gap introduces a suppression ofthe startle response (middle row). In animals with tinnitus, the gap isfilled by the tinnitus (bottom row) and the startle response shows lessreduction relative to the no gap startle response (top row arrow).

FIG. 10B illustrates a histogram of the normalized startle distribution(white line) partitioned into two distributions: no evidence fortinnitus (left bars) and evidence for tinnitus (right bars).

FIG. 10C illustrates a plot of the posterior probabilities thatnormalized startle values belong to the tinnitus or non-tinnitusdistributions.

FIG. 10D illustrates a histogram of the partitioned distribution ofpost-exposure normalized startle observations for sham animals.

FIG. 10E illustrates a histogram of the partitioned distribution ofnormalized startle observations for baseline (pre-exposure) observationsfrom sham and exposed animals.

FIG. 10F illustrates a histogram of the partitioned distribution ofpost-exposure normalized startle observations from exposed animals.

FIG. 11A-11D illustrate plots of ABR threshold shift versus frequencyfor the left (exposed) and right (unexposed) ear for a noise-exposedgroup of subjects and for a sham group of subjects, in accordance withan example.

FIG. 12A illustrates percent of sham (white bars) and exposed (blackbars) guinea pigs that show evidence for tinnitus in different frequencybands.

FIG. 12B illustrates a normalized startle response amplitudes in eachfrequency band for exposed animals (black bars) compared to sham animals(white bars).

FIG. 12C illustrates a normalized startle response amplitudes in eachfrequency band for tinnitus animals (ET) compared to animals withouttinnitus (ENT) and sham animals.

FIG. 13A illustrates two examples of single-unit Hebbian timing rules,one from a sham and one from a noise-exposed guinea pig. A cartoon atthe top of the panel demonstrates the relative order of Sp5 and soundstimuli. A vertical line in the cartoon represents the Sp5 stimulus andthe sinusoid represents the tone stimulus.

FIG. 13B illustrates two examples of single unit anti-Hebbian timingrules, one from a sham and one from a noise-exposed guinea pig.

FIG. 13C illustrates the percent of principal units that showedHebbian-like (H), anti-Hebbian-like (aH), enhancing (E) and suppressing(S) timing rules from sham (left) and noise-exposed (right) animals.Stacked bars indicate units from below (black), within (white), andabove (grey) the damaged frequency region.

FIG. 13D illustrates timing rules shifted from Hebbian in sham animalsto anti-Hebbian in exposed animals. Mean timing rules showing bimodalplasticity of sound-evoked firing rates for units from sham and exposedguinea pigs.

FIG. 14A illustrates mean timing rules showing bimodal plasticity ofsound-evoked firing rates for units from sham, ENT, and ET guinea pigs.A cartoon at the top of the panel demonstrates the relative order of Sp5and sound stimuli, where a vertical line represents the Sp5 stimulationand the sinusoid represents the tone stimulus.

FIG. 14B illustrates the percent of units that showed Hebbian-like (H),anti-Hebbian-like (aH), enhancing (E) and suppressing (S) timing rulesfrom sham (left), ENT (middle) and ET (right) animals.

FIG. 15A illustrates spontaneous firing rates before any bimodalstimulation for each unit as a function of each unit's best frequencyfor sham, ENT, and ET units.

FIG. 15B illustrates mean spontaneous rates for units with bestfrequencies below 12 kHz.

FIG. 15C illustrates mean spontaneous rates for units with bestfrequencies above 12 kHz.

FIG. 15D illustrates a mean timing rules show bimodal plasticity ofspontaneous firing rates for units from sham, ENT, and ET guinea pigs.

FIG. 16 is a plot of a distribution of responses to Sp5 stimulation fordifferent test groups (sham, ET, and ENT), in accordance with anexample.

FIG. 17A illustrates an example hardware system for implementing thetinnitus reduction techniques described herein, in accordance with anexample.

FIG. 17B illustrates a software platform that may be executed byinstructions on a computer to implement techniques described herein, inaccordance with an example.

FIG. 18 illustrates an exemplary bimodal stimulation system forperforming the techniques described herein, in accordance with anexample.

DETAILED DESCRIPTION

Generally, examples are described for providing multisensory stimuli toreduce or eliminate phantom sound perception or tinnitus. Stimulation ofboth the somatosensory system and the auditory system is achieved, butin a counterintuitive, timed manner, in which spacing between auditoryand somatosensory stimuli is used to activate spike-timing dependentplasticity in target neurons in such a manner that spontaneous activityis reduced, thereby reducing or removing tinnitus.

Conventional bimodal stimulation techniques relied upon simultaneousstimulation of systems, with the belief that contemporaneous triggeringof vagal nerve stimulation, to stimulate neuromodulatory inputs toauditory cortex from nucleus basalis, with sound stimulation would treatsuch conditions as tinnitus by triggering remapping of the corticaltopographic frequency map. Recent studies have shown that corticalremapping is not necessary for tinnitus. To develop the presenttechniques, however, bimodal plasticity induction in the DCN wasassessed in vivo in a different manner, by measuring sound-evoked andspontaneous firing rates before and after bimodal stimulation, andwhere, in these examples, the second system stimulated is thesomatosensory system.

FIG. 1A is an example multisensory stimulation configuration 100 forbimodal stimulation of two different types of synapses. FIG. 1A showsdifferent cell types that connect with each other (Gr=granule cells;St=stellate cells). Stimulation of the somatosensory system is achievedthrough electrical pulses 102, in this example, delivered to 5p5 toactivate parallel fiber-fusiform (Fu) (e.g., at the face and part of thesomatosensory system—the parallel fibers connect the somatosensorysystem with the cochlear nucleus fusiform and cartwheel cells) andcartwheel cell (Ca) synapses (e.g., part of the cochlear nucleus),paired with a 50-ms tone burst 104 to the auditory system to elicitspiking activity in the fusiform (Fu) and cartwheel (Ca) cells. Dorsalcochlear nucleus unit responses to unimodal tones and spontaneousactivity following bimodal stimulation were recorded with amulti-channel electrode 106 placed into the DCN using a standardprotocol.

FIG. 1B illustrates an example protocol 200 for implementation of thebimodal stimulation, through the use of a bimodal pairing protocol. Foreach of the bimodal stimulation pairings in FIG. 1B a correspondingfiring rate plots shown in FIG. 1C. As shown, the present techniques areable to suppress, in some examples, and enhance, in others, responses tosounds through bimodal stimulation. As represented in FIG. 1C, forexample, bimodal stimulation, in particular the relative timing of suchstimuli, has been adjusted such that the spontaneous activity andresponses to tones (initially 202) were suppressed for 5 min (206), 15min (208), and 25 (210) mins after bimodal stimulation (204), underdifferent firing conditions. This resulted in the plots in FIG. 1C.Bimodal enhancement and suppression, in examples herein, were measuredby comparing unimodal (auditory) response magnitudes at different timesafter bimodal stimulation to unimodal response magnitudes before bimodalstimulation. These are equivalent to the “late” or long-lasting changespreviously described in Dehmel et al., 2012 that reflect plasticity.This “bimodal plasticity” contrasts with bimodal integration in whichbimodal enhancement and suppression were measured by comparing responsesduring bimodal stimulation with unimodal (auditory) responses.

In any event, in some examples, the present techniques includestimulating with auditory and somatosensory stimuli and then waiting atime period to observe that the effects are still there. The resultsshow the long-lasting effect necessary to induce long-lastingsuppression of tinnitus and may be contrasted with immediate effects,which are less relevant to tinnitus suppression.

As we have shown, bimodal plasticity is stimulus-timing dependent. Invivo stimulus timing dependent plasticity has been shown to reflectunderlying Hebbian and anti-Hebbian spike timing dependent plasticity(STDP). To assess stimulus-timing dependence for our techniques, in anexample, the bimodal stimulation protocol (FIG. 1B) was repeated withvarying bimodal intervals, e.g., 5p5 stimulation onset minus soundonset. As illustrated in the example of FIG. 2A, which shows plots ofauditory response for different timings between the somatosensorystimulation and the auditory stimulation, the auditory response wassuppressed after bimodal stimulation when somatosensory systemstimulation (5p5) preceded the auditory stimulation, but the auditoryresponse was enhanced if the auditory stimulation preceded thesomatosensory stimulation. This corresponds to values for bimodalinterval (BI) below 0 ms (e.g., −40 ms, −20 ms, −10 ms) and values forBI above 0 ms (10 ms, 20 ms, and 40 ms), respectively, i.e., wherenegative bimodal intervals indicate somatosensory stimulation precedesthe auditory stimulation, and positive bimodal intervals indicateauditory preceding somatosensory stimulation. Bimodal plasticity wasconsidered stimulus-timing dependent when the sound-evoked firing ratesincreased or decreased following bimodal stimulation at some, but notall, of the bimodal intervals tested. What we found was that all unitsin which responses to sound were modulated by the bimodal pairingprotocol showed stimulus-timing dependence (i.e., the firing rateincreased or decreased by at least 20% following at least one bimodalinterval tested). The particular amount of increase or decrease infiring rate may be adjusted as discussed herein; of course, thisparticular amount is provided by way of example.

For each unit demonstrating stimulus-timing-dependent plasticity, atiming rule was constructed from the percent change in firing rate as afunction of bimodal interval. The timing rules are illustrated in FIGS.2B-2E, and correspond to those of FIG. 1B with plots for 5 mins (220),15 mins (222), and 25 mins (224) after exposure to the bimodalstimulation. Timing rules were classified into Hebbian-like (FIG. 2B),anti-Hebbian-like (FIG. 2C), enhanced (FIG. 2D), and suppressed (FIG.2E). Mean single unit timing rules for each group are shown in FIGS.2F-2I, with corresponding identifies. As shown, Hebbian-like units weremaximally enhanced when the somatosensory stimulation preceded auditorystimulation and maximally suppressed when auditory stimulation precededsomatosensory stimulation, likely reflecting Hebbian STDP at theparallel-fusiform cell synapse (n=5; FIGS. 2B and 2F). Anti-Hebbian-likeunits were maximally suppressed when somatosensory stimulation precededauditory stimulation and maximally enhanced when auditory stimulationpreceded somatosensory stimulation (n=7; FIG. 2C, 2G), likely reflectinga combination of Hebbian STDP at the parallel-fusiform cell synapse andanti-Hebbian STDP at the parallel-cartwheel synapse. Other units wereeither enhanced (n=2; FIGS. 2D, 2H) or suppressed (n=2; FIGS. 2E, 2I) byall bimodal pairing protocols. Although not shown, comparison of singleand multi-unit clusters, meaning that with the present techniques we canrecord from one or more neurons using these electrodes and then we canseparate some of them into single neuron (unit) responses usingprincipal component analysis, indicated that the same Hebbian-like(n=25), anti-Hebbian-like (n=18), enhanced (n=18), suppressed (n=12)timing rules were observed in multi-unit clusters. Thirty three multiunits showed a complex dependence of suppression and enhancement on thebimodal interval (not shown).

Synaptic plasticity at parallel fiber synapses in the DCN develops overthe course of several minutes. To compare the bimodal plasticity timecourse to synaptic plasticity time courses, bimodal plasticity wasmeasured at 5, 15, and 25 minutes after bimodal stimulation, using theprotocol of FIG. 1B, for both single and multi-units. The maximalenhancement and suppression and the bimodal interval that inducedmaximal enhancement and suppression were used to estimate the effect ofbimodal stimulation on the DCN neural population. The change in firingrate following bimodal stimulation was often greater at 15 or 25 minutesthan at 5 minutes after bimodal stimulation (see, e.g., FIG. 2B-E).Maximal bimodal enhancement plateaued 15 minutes following bimodalpairing and started to recover at 25 minutes, as shown in FIG. 3A (top).In contrast, maximal bimodal suppression continued to develop over 25minutes as shown in FIG. 3A (bottom). Median maximal suppression was−28% (n=126) after 25 minutes while median maximal enhancement was 40%(n=126) by 25 minutes after bimodal pairing. These data indicate thattone responses began to recover towards baseline 25 minutes afterapplication of the bimodal stimulus pairing. This performance isprovided by way of example, however. In some examples, responses totones recovered to baseline levels within 90 minutes after the bimodalpairing (see, e.g., FIG. 3B).

To determine the proper timing and order of bimodal stimulation of thesomatosensory and auditory systems, a firing rate mapping, like that ofFIGS. 2F-2I and FIG. 3A, may be used to assess stimulus-timing dependentplasticity. In the illustrated example, the DCN neural population isdominated by anti-Hebbian-like stimulus-timing dependent plasticity.Having a technique to identify the maximum bimodal enhancement andsuppression with corresponding bimodal intervals allowed a populationestimate of the stimulus-timing dependence of bimodal plasticity in theDCN. An example is shown in FIG. 4. When the most effective bimodalpairing protocol (e.g., bimodal interval) consisted of Sp5(somatosensory stimulation) following (auditory) tone stimulation by 20or 40 ms, Sp5 synchronous with tone stimulation, or Sp5 preceding tonestimulation by 10 ms, bimodal stimulation was most likely to produceenhancement. In contrast, when the most effective bimodal stimulationprotocol was Sp5 preceding the tone stimulation by 20 or 40 ms orfollowing tones by 10 ms, induced bimodal suppression resulted.

We also found that our bimodal stimulation techniques induced strongerpersistent effects than unimodal stimulation. Attendant to our proposedhypothesis that STDP underlies long-lasting bimodal plasticity is thatpaired auditory and somatosensory stimulation induce long-lastingsuppression or enhancement of tone-evoked responses. To test this,changes in unimodal tone-evoked responses were measured during protocolsin which the bimodal stimulus was replaced by a unimodal stimulus (i.e.,with either sound or Sp5 stimulation alone). FIGS. 5A and 5B illustratethe change in firing rate for bimodal stimulation versus unimodal tonestimulation (FIG. 5A) and unimodal somatosensory stimulation (FIG. 5B),respectively. Maximal bimodal enhancement and suppression weresignificantly stronger than enhancement or suppression of thetone-evoked response following unimodal tone stimulation (FIG. 5A).However, only maximal suppression, and not enhancement, followingbimodal stimulation was stronger than that following unimodal 5p5stimulation (FIG. 5B). Thus, activation of both somatosensory andauditory inputs has a greater long-lasting effect on DCN unit responsesthan either activation of auditory or somatosensory inputs alone.

We found from our testing of variations to timing and ordering ofbimodal stimuli, that units excited by Sp5 stimulation exhibited Hebbiantiming rules while units inhibited by Sp5 stimulation exhibitedanti-Hebbian timing rules. Activation of somatosensory neurons haspreviously been shown to elicit excitation, inhibition, or complexresponses in DCN neurons. Somatosensory stimulation elicits eitherexcitatory or inhibitory responses in a particular fusiform celldepending on whether input is conveyed to that fusiform cell directlyfrom parallel fiber inputs or via inhibitory interneurons (cartwheelcells). Although 5p5 stimulation amplitude was selected to activatesub-threshold somatosensory inputs, eleven units had measurableexcitatory or inhibitory responses to unimodal 5p5 stimulation andclearly defined Hebbian or anti-Hebbian timing rules. For example, in anexample, we measured this by examining the effect of somatosensorystimulation on the sound-evoked response. If it affected the responsebut elicited no response on its own, this was defined as sub threshold.Five out of six units that responded to 5p5 stimulation with excitatoryresponses exhibited Hebbian timing rules, suggesting that Hebbian timingrules were driven by parallel fiber-to-fusiform cell synapses (FIGS. 6Aand 6B). In contrast, four out of five units that responded to 5p5stimulation with inhibition exhibited anti-Hebbian timing rules,suggesting anti-Hebbian dependence on parallel fiber-to-cartwheel cellsynapses (FIGS. 6C and 6D). Units that did not show clearstimulus-timing dependency were just as likely to be excited orinhibited by 5p5 stimulation alone (not shown).

We also found that bimodal stimulus timing rules correlated withinhibitory inputs, inhibitory inputs are those neural connections fromother neurons that decrease the response rate of the neuron in question.To examine this, units were classified according to traditionalphysiological response schemes for a guinea pig by their frequencyresponse maps (n=63 units; types 1,11,111, I-111, IV, and IV-T), wheretypes refer to the amount of inhibition that is reflected in theresponse of the units to sound, and Type 1 has the least inhibition,Type IV has the most, and their temporal responses properties at a bestfrequency (n=66 units; buildup, pause-buildup, chopper, onset, andprimary-like). These physiological response properties are linked tointrinsic, morphological, and network properties of DCN neurons,including their somatosensory innervation. We found that the proportionof units with Hebbian and anti-Hebbian-like timing rules correlated withthe degree of inhibition reflected in their response areas. FIG. 7A, forexample, shows the proportion of Hebbian and anti-Hebbian-like units fortypes I, I-III, III, and IV, response map classifications usuallyassociated with fusiform or giant cells. Hebbian-like timing rules weremore likely to be found in units with Type I response areas with noinhibition than in units with Type III or IV response areas withsignificant inhibition away from a best frequency or at highintensities. Thus, units with less inhibition tended to follow Hebbianrules and those with more inhibition tended to follow anti-hebbianrules.

Timing rules and the strength of bimodal plasticity were also comparedfor groups of units with each combination of the temporal and receptivefield response types. Two classes of neurons had consistent bimodaltiming rules. Buildup or pauser-buildup units with type I or type IIresponse areas exhibited clear Hebbian-like timing rules (FIG. 7B). Incontrast, onset units with type IV or IV-T response maps exhibited onlyanti-Hebbian timing rules (FIG. 7C).

We also determined that spontaneous rate changes correlate with changesin sound-evoked firing rate. After bimodal stimulation the changes insound-driven and spontaneous firing rates were significantly correlatedfor all bimodal intervals except for −20 ms (0.21<R2<0.48). The highestcorrelation in sound-driven and spontaneous firing rates was observedfollowing the +10 ms bimodal interval (FIG. 8, linear regressionanalysis, DF=82; R2=0.48; p=2.62e−13). However, changes in sound-evokedand spontaneous firing rates were not significantly correlated followingbimodal stimulation at an interval of −20 ms.

It is believed that part of the reasoning behind the unexpected resultsherein is the influence of network and intrinsic properties on bimodalplasticity. For example, the timing rule continuum, from Hebbian-like toanti-Hebbian-like to complex, developed herein seems to result from thevariety of DCN neural types and suggests that intrinsic or networkmechanisms act alongside STDP to control bimodal plasticity. We alsobelieve that bimodal plasticity timing rules may also be influenced bycholinergic input from the superior olivary complex or the tegmentalnuclei, which modulate STDP in the DCN, converting Hebbian LTP toanti-Hebbian LTD at parallel fiber-fusiform cell synapses.

Our determination that physiological classes of DCN neurons exhibitdiffering stimulus-timing dependencies implies that physiological (andlikely morphological) subtypes of DCN neurons perform differentfunctions with their multimodal inputs. Our data indicates that DCNneurons with less inhibitory influence (Type I receptive fields) aremore likely to display Hebbian-like stimulus timing dependence whilethose with significant inhibitory influence (Type III and IV receptivefields) are more likely to display anti-Hebbian-like stimulus timingdependence. This may reflect inhibitory influences from vertical cell orcartwheel cells on post-synaptic spiking patterns which, in fusiformcells, are likely determined by long-lasting or pre-hyperpolarizinginhibition. The timing rules for STDP induction in other systems dependnot only on the relative timing of pre-synaptic activity andpost-synaptic spikes, but also on the number and pattern ofpost-synaptic spikes.

Alternatively, the source of sound-driven inhibition to DCN principalcells may also exhibit predominantly Hebbian-like stimulus-timingdependent plasticity, resulting in anti-Hebbian-like timing rules inrecipient neurons. One source could be type II neurons, putativevertical cells. Type II neurons supply inhibition to fusiform and giantcells, are inhibited by somatosensory and parallel fiber input, and aswe've found exhibit Hebbian-like stimulus-timing dependent plasticity.

Hebbian and anti-Hebbian STDP are important mechanisms for adaptiveprocessing in cerebellar-like circuits. Neural responses to stimuli inthese circuits exhibit long-lasting adaptation induced by correlationsbetween primary sensory input and error signals supplied by motorcontrol or secondary sensory inputs. We describe the first in vivoexperiments evaluating mechanisms for multisensory adaptive processingin the DCN. Thus, we show that adaptive processing in the DCN is amechanism to suppress responses to sound predicted by non-auditorysignals, such as self-generated sound preceded by somatosensory input.While various techniques are described herein, including techniques fordetermining optimum ways to reduce tinnitus, hyperacusis, and the like,numerous variations are contemplated and will be apparent to persons ofordinary skill upon reading this disclosure. For example, the techniquesmay also adapt sound localization signals in the DCN to pinna or headposition. A high proportion of DCN neurons exhibited anti-Hebbian-liketiming rules, with responses to tones suppressed when 5p5 stimulationpreceded the tone and enhanced when the tone preceded 5p5 stimulation.This observation is consistent with the hypothesis that DCN neuronscancel self-generated sounds predicted by preceding somatosensoryactivation.

Reports of elevated spontaneous firing rates in the DCN aftertinnitus-inducing noise, implicates this structure as a site of phantomsound, or “tinnitus”, generation in animal models of tinnitus. BecauseDCN neurons are more responsive to somatosensory stimulation followinghearing damage, bimodal plasticity in DCN is believed to play a role insomatic tinnitus, i.e., the modulation of the pitch and loudness of aphantom sound perception by pressure or manipulation of the head andneck. In fact, as we've shown, the effect of bimodal stimulation, e.g.,with 5p5 preceding tone stimulation, shifts from suppression in normalanimals to enhancement in guinea pigs with behavioral evidence oftinnitus, which suggests that bimodal plasticity may contribute to DCNhyperactivity in tinnitus.

First Example Testing Protocols: The experimental procedures used forone set of example testing procedures, corresponding to FIGS. 1A-C, arenow described. Animals: Male pigmented guinea pigs (n=5) from theUniversity of Michigan colony (300-400 g; Ann Arbor, Mich.) were used.Surgical approach and electrode placement: Guinea pigs were anesthetized(S.D., ketamine and xylazine; 40 mg/kg, 10 mg/kg) and their heads fixedin a stereotaxic frame using a bite bar and hollow ear bars placed intothe ear canals. Core temperature was maintained at 38° C. A leftcraniotomy was performed and a small amount of cerebellum was aspirated(leaving paraflocculus intact) to allow for visual placement of therecording electrode. Supplemental doses of ketamine and xylazine (I.M.)were administered at least hourly when indicated by response to a toepinch. The guinea pig's condition was monitored by assessment of bodytemperature, respiration and heart rates, and unit thresholds.

A concentric bipolar stimulating electrode (FHC, Bowdoin, Me.) wasdipped in fluorogold and placed stereotaxically into 5p5; −10 degreesbelow horizontal, 0.28+/−0.03 cm lateral from midline; 0.25+/−0.02 cmcaudal from transverse sinus; 0.9+/−0.1 cm below surface of cerebellum.The location of the electrode was reconstructed post-mortem. Afour-shank, thirty two-channel silicon-substrate electrode (sitespacing=100 um, shank pitch=250 um, site area=177 um2, impedance=1-3mOhms, available from NeuroNexus, Ann Arbor, Mich.) was placed at theDCN surface with each medial-to-lateral shank positioned within adifferent iso-frequency layer. The electrode was then lowered 0.8-1.0 uminto DCN until the uppermost site on each shank responded to sound. Inone guinea pig, after completing the recording protocol the DCNelectrode was moved to a more medial location and a new frequency wasselected for stimulation while the 5p5 stimulating electrode remained inplace.

Auditory and somatosensory stimulation: Neural activity in response tounimodal tones was recorded before and at 5, 15, and 25 minutes afterthe bimodal stimulation protocol (FIG. 1B). Tone signals (50 msduration) gated with a cosine window (2 ms rise/fall time) weregenerated using Open Ex and an RX8 DSP (TDT, Alachula, Fla.) with 12 bitprecision and sampling frequency set at 100 kHz. Sound was delivered tothe left ear through the hollow ear bar by a shielded speaker (DT770,Beyer) driven by an HB7 amplifier (TDT, Alachula, Fla.). The systemresponse was measured using a condenser microphone attached to thehollow earbar by a ‘A” long tube approximating the ear canal. Soundlevels were adjusted to account for the system response using aprogrammable attenuator (PA5, TDT, Alachula, Fla.) to deliver calibratedlevels (dB SPL) at frequencies from 200 Hz to 24 kHz.

The bimodal stimulation protocol included 500 trials of the 50 ms tonescombined with electrical activation of 5p5 locations known to project toDCN. Five biphasic (100 us/phase) current pulses at 1000 Hz weredelivered to 5p5 through a concentric bipolar electrode using a customisolated constant current source. The current amplitude was set to thehighest level (range: 50-70 IA) that did not elicit movement artifact.The tone level (60-65 dB SPL) and frequency were fixed for the durationof the recording and were selected to reliably elicit responses to soundfrom most recording sites. The bimodal interval was defined as the onsetof the 5p5 stimulus minus the onset of the tone, with negative valuesindicating 5p5-leading tone stimulation and positive values indicatingtone-leading 5p5 stimulation. Varied bimodal intervals were used toassess stimulus-timing dependence of bimodal plasticity. During eachrecording session, the bimodal interval was randomly selected from thefollowing intervals until all conditions were tested: −40, −20, −10, 0,+10, +20, +40, or +60 ms. For the unimodal control protocols, either thecurrent amplitude was set to 0 uA or the sound level was set to 0 dBSPL.

Spike detection and sorting: Voltages recorded from the multi-channelrecording electrode were digitized by a PZ2 preamp (Fs=12 kHz, TDT,available from Alachua, Fla., USA) and band-pass filtered (300 Hz-3 kHz)before online spike detection using a fixed voltage threshold set at 2.5standard deviations above background noise (RZ2, TDT, Alachua, Fla.,USA). Spike waveform snippets and timestamps were saved to a PC usingOpen Explorer (TDT, Alachua, Fla., USA). Waveform snippets were sortedusing principal components of the waveform shape and K-means clusteranalysis with fixed variance (95%) and 5 clusters (OpenSorter, TDT,Alachua, Fla., USA). Clusters with a J2 value above Ie-5 were notconsidered well isolated and were combined. Single units were identifiedby consistency of waveform shape and amplitude. Spikes up to 15 ms afterthe onset of the current stimulation were contaminated by electricalartifacts and ringing and excluded from all analyses. While multi-unitclusters could not be identified as isolated single units, the waveformshapes, amplitudes, and response properties were consistent over theduration of the recording.

Experimental design: To characterize unit responses to sound accordingto standard classification schemes, tone stimuli were presented beforeany 5p5 stimulation. Tone levels (0-85 dB SPL; 5 dB steps) andfrequencies were varied (200 Hz-23 kHz; 0.1 octave steps) between trials(200 ms trial; 50 ms tone) with each condition repeated 10-20 times. Thecurrent amplitude for 5p5 stimulation was set at the highest amplitudethat did not elicit ipsilateral facial twitches (60-80 IA). At thecurrent amplitude presented, few units showed supra-threshold responsesto somatosensory stimulation, but clearly sub-threshold responses wereelicited, as evidenced by the bimodal effects.

Unimodal trials were recorded at four time points: before, and 5, 15,and 25 minutes after the bimodal stimulation protocol (FIG. 1B).Responses were recorded to unimodal tones (TONE) presented at the samelevel (60-65 dB SPL) as in the bimodal stimulation protocol (200 trials,5 trials per second). Two minutes of spontaneous activity (SPONT) wasalso recorded at each time point before and after the bimodalstimulation protocol. All unimodal tones and rate level functions wereat the same frequency used for bimodal stimulation. The entire recordingblock in FIG. 1B (the combined pairs 202-210) lasted for 30-35 minuteswith unimodal recordings at each time point lasting for 5-7 minutes andthe bimodal stimulation protocol lasting for 4-5 minutes. The recordingblock in FIG. 1B was repeated randomly for each bimodal interval tested(−40, −20, −10, 0, 10, 20, 40, or 60 ms). In one guinea pig, controlrecording blocks were repeated in which unimodal tone or Sp5 stimulireplaced the bimodal stimuli. After the final recording block, theresponses to unimodal tones were measured every 15-30 minutes for aslong as possible to assess recovery after bimodal stimulation.

Unit characterization: All units were characterized by best frequency,threshold, frequency response map and temporal response patterns at bestfrequency. Response maps were constructed by computing the sound-evokedfiring rate during the 50 ms tone minus spontaneous firing rate measuredduring the last 50 ms of each trial. Excitation or inhibition wasconsidered significant when the firing rate was greater than 2.5standard deviations above or below the mean spike rate of all trialswith no sound. Post-stimulus time histograms were constructed for eachunit from 50-200 trials with the tone level 10-30 dB above threshold andfrequency within 0.1 octave of the identified best frequency. Unitclassification by receptive field and post-stimulus time histogramprovide indirect evidence for the synaptic drive and intrinsicprocessing, respectively, of individual neurons in DCN.

FIGS. 9-16 result from other example testing that we performed to usestimulus-timing dependent bimodal plasticity to assess STDPmetaplasticity in a guinea pig model of tinnitus. We found that bimodalplasticity timing rules were broader and more likely to be anti-Hebbianin guinea pigs with tinnitus than in sham guinea pigs or those withouttinnitus after noise damage, which suggests that tinnitus may be linkedto metaplasticity of STDP in the DCN.

As discussed further below, in this example protocol testing, guineapigs were exposed to a narrowband noise that produced a temporary shiftin auditory brainstem response thresholds known to produce tinnitus.Sixty percent of guinea pigs developed tinnitus according to behavioraltesting by gap-induced prepulse inhibition of the acoustic startle.Following noise-exposure and tinnitus induction, stimulus-timingdependent plasticity was measured by comparing responses to sound beforeand after paired somatosensory and auditory stimulation with varyingintervals and orders. What we found was that timing rules in animalswith verified tinnitus were broader and more likely to be anti-Hebbianthan timing rules in sham animals or noise-exposed animals that did notdevelop tinnitus. Furthermore, exposed animals with tinnitus had weakersuppressive responses than either sham animals or exposed animalswithout tinnitus. Broader timing rules combined with weaker bimodalsuppression in animals with tinnitus suggested that somatosensory inputsto the DCN have a strengthened, enhancing effect in tinnitus. Theseresults suggested that tinnitus development was linked to DCNspike-timing dependent plasticity, and thus provided furtherconfirmation of what we described above that the present techniquesprovide potential tinnitus therapies.

As demonstrated, STDP in animals with tinnitus is compared to thoseanimals without tinnitus. That these further experiments furtherdemonstrated that the techniques herein, such as ways in which one canchange the firing rate in the DCN using bimodal stimulation based on theordering and spacing, can be used to find the specific orders andintervals of bimodal stimulation that lead to a decrease in firing rateof the majority of neurons that send the signal to the auditory cortex.Thus these further experiments provide additional examples in neuronsthat may be contributing to the tinnitus percept of specific timingrules and techniques for determining timing rules that create increasesor decreases in such firing rates. From these timing rules, we can takethose rules that decrease the firing rates to treat tinnitus. Forexample, the role of bimodal STDP in the DCN is to identifyspatiotemporal patterns in auditory nerve activity correlated withsomatosensory inputs. In the normal system, narrow STDP timing rulesheighten or suppress the responsivity of DCN neurons to auditory nerveinputs that are tightly correlated with somatosensory events. Broadertiming rules in tinnitus animals would increase the likelihood of asomatosensory event triggering anti-Hebbian or Hebbian plasticity,leading to heightened responsivity to spontaneous, as well as driven,auditory nerve spiking patterns. The resulting hyperactivity could be aneural representation of tinnitus. This mechanism may act cooperativelywith the decreases in granule cell resistance observed after noiseexposure that further enhance the strength of somatosensory inputs.Furthermore, the corresponding decrease in bimodal suppression intinnitus animals would further enhance the hyperactivity. Thetinnitus-associated changes in bimodal stimulus-timing dependentplasticity suggest that somatosensory inputs have a greater influence onDCN neural activity in animals that developed tinnitus than in thosethat did not. A similar process is found in visual cortex, wherebroadened STDP timing rules after visual deprivation cause long-termpotentiation of spontaneous inputs to visual cortex at lower spontaneousfiring rates than in the normal visual cortex.

From this example, we noticed a number of effects from endemic to shiftsin bimodal stimulation effects over certain frequency ranges, which isparticular useful as the frequency range for a patients tinnitussensitivity will vary from patient to patient, making identifying usefuloperating ranges of bimodal stimulation important.

We demonstrated that narrow-band noise exposure centered at 7 kHzinduced temporary threshold shifts between 7 and 16 kHz. Noise exposureinduced a TTS as demonstrated by auditory brainstem response (ABR)thresholds. For example, ABR thresholds in the exposed ear (FIG. 11A)but not the unexposed ear (FIG. 11B) were elevated immediately afterexposure and recovered to baseline by 1 week after noise exposure.Maximum threshold elevation was 35 dB (mean)+/−3.5 dB (s.d.) at 9 kHzafter the first exposure and 19 dB (mean)+/−2.1 dB (s.d.) at 10 kHzafter the second exposure with thresholds elevated in a band from theexposure frequency to 2 octaves above the exposure frequency. ABRthresholds in sham-exposed guinea pigs were not elevated above baselinein either ear (FIG. 11C and FIG. 11D). Data for post exposure 1 (230),recovery 1 (232), post exposure 2 (234), and recovery 2 (236), and final(238) are all shown.

We also demonstrated that exposure to narrowband noise induced tinnitusin the 12-14 kHz band in 60% of guinea pigs. Gap-induced prepulseinhibition of acoustic startle (GPIAS) was used to assess each guineapig for evidence of a frequency specific tinnitus percept. Duringbaseline startle testing, all guinea pigs exhibited normal gap detectionwith smaller startle responses when there was a gap than when there wasno gap. All guinea pigs exhibited normalized startle responses below 0.5during baseline, with the normalized startle response defined as theratio of the startle response amplitude with gap prepulse (AG) to thestartle response amplitude without gap (ANG). Impaired gap detection,which was considered evidence for tinnitus, was identified bysignificantly elevated normalized startle responses. Following theTTS-inducing noise exposure, 60 percent of exposed guinea pigs wereidentified as having tinnitus in the 12-14 kHz band, half of which alsoshowed evidence for tinnitus in either the 4-8 kHz, 8-10 kHz, or 16-18kHz bands (FIG. 12A). Guinea pigs with evidence for tinnitus in the12-14 kHz bands were thus placed into the Exposed with Tinnitus (ET)group. The remaining 40% of exposed guinea pigs that showed no evidencefor tinnitus in any tested frequency band were placed into the Exposedwith No Tinnitus (ENT) group, while the sham animals were considered asa separate group (Sham).

To validate the ET and ENT groupings, gap detection ability was comparedbetween all exposed and sham guinea pigs (FIG. 12B), and between the ET,ENT and sham guinea pigs (FIG. 12C). The normalized startle response wasnot significantly elevated for any frequency band in all exposed guineapigs (FIG. 12B). However, normalized startle responses weresignificantly elevated, indicating impaired gap detection ability, forthe 4-6, 8-10, and 12-14 kHz bands in the ET group but not in the ENTgroup (FIG. 12C). The normalized startle response was not significantlyelevated for the BBN background signal or the 16-18 kHz backgroundsignal either in the ET group or the ENT group (FIG. 12C).

We found that bimodal plasticity timing rules were predominantlyanti-Hebbian and suppressing in noise-exposed animals. We measured thestimulus-timing dependence of bimodal plasticity and demonstratedpredominantly Hebbian-like timing rules in normal animals. In order toseparate noise-exposure driven changes in neural mechanisms from thoseassociated with tinnitus, stimulus-timing dependent bimodal plasticitywas first compared between principal cell units from Sham (n=100 units)and Exposed (n=288 units) guinea pigs and then between exposed animalsthat developed tinnitus (ET) or did not develop tinnitus (ENT). Bimodalplasticity was assessed by identifying significant changes insound-evoked average firing rates 15 minutes after bimodal stimulation.The dependence of bimodal plasticity on stimulus timing was confirmed byrepeatedly measuring bimodal plasticity using the protocol in FIG. 1Aand varying the bimodal interval (10, 20, and 40 ms) and order (Sp5 ortone leading) in the bimodal pairing protocol. Bimodal intervals wereclassified as eliciting significant bimodal plasticity if the firingrates before and 15 minutes after were significantly different (t-test,p<0.05).

Timing rules were constructed for each unit by plotting the change insound-evoked firing rates observed 15 minutes after various bimodalpairing orders and intervals. These timing rules were classified asHebbian-like (n=132; examples from sham and noise-exposed animals shownin FIG. 13A), anti-Hebbian-like (n=69; examples from sham andnoise-exposed animals shown in FIG. 13B), enhancing (n=44), orsuppressing (n=143). In units with Hebbian-like timing rules,sound-evoked firing rates increased after bimodal stimulation when Sp5stimulation preceded tone onset and decreased after bimodal stimulationwhen Sp5 stimulation followed tone onset (FIG. 13A). Note that thetemporal window for enhancing bimodal plasticity is broader in this unitfrom a noise-exposed animal from the ET group, with enhancement observedafter bimodal intervals of −10, 10, and 20 ms. In contrast, in the unitfrom the sham animal enhancement is only observed with bimodal intervalsof 10 and 20 ms. In units with anti-Hebbian-like timing rules,sound-evoked firing rates increased 15 minutes after Sp5 stimulationfollowed tone onset and decreased 15 minutes after Sp5 stimulationpreceded tone onset (FIG. 13B). Responses in the remaining units wereonly enhanced or suppressed following bimodal stimulation at the testedbimodal intervals (individual units not shown).

Units from sham animals were distributed among the timing rule classesin proportions similar to normal animals, with most units showingHebbian-like timing rules (FIG. 13C, left column). In contrast, afternoise exposure, units with anti-Hebbian and suppressive timing ruleswere significantly more prevalent (Chi Squared proportion test; Sham vs.Exposed; DF=3; Chi²=25.2564; p<0.0001) than Hebbian or enhancing units(FIG. 13C, right column). Further breakdown of units into those with BFswithin the TTS frequency region (8-16 kHz) and those outside theseregions (below 8 kHz and above 16 kHz) reveal that units within the TTSfrequency region comprised the highest percentages of units in theanti-Hebbian class.

Mean timing rules estimate the effect of somatosensory-auditory pairingat specific intervals on DCN population activity. Mean population timingrules from all sham and exposed units 15 minutes after bimodalstimulation revealed a shift in the population timing rules fromHebbian-like to anti-Hebbian-like in the noise-exposed animals (FIG.13D). In sham animals, the mean population timing rule was Hebbian-like,with enhancement of sound-evoked firing rates when Sp5 preceded soundstimulation (positive values) and suppression when Sp5 stimulationfollowed sound stimulation (negative values; FIG. 13D, sham). Innoise-exposed animals, the reverse occurred, with suppression ofsound-evoked firing rates for Sp5 preceding sound stimulation andenhancement with Sp5 following sound stimulation (FIG. 13D, exposed). Atwo-way ANOVA with exposure group (Group) and bimodal interval (BI)revealed a significant main effect of bimodal interval and a significantinteraction between bimodal interval and exposure group(Group−F(1)=1.38, p=0.240; BI−F(5)=5.37, p<0.001; Exposure Group×BimodalInterval−F(5)=14.47, p<0.001). Bimodal intervals for which there weresignificant differences between exposure groups according toTukey-Kramer's post-hoc tests are designated in FIG. 13D by stars.

We found that anti-Hebbian bimodal enhancement was broader in guineapigs exhibiting tinnitus, while suppressive bimodal plasticity wasbroader in animals without tinnitus. To establish tinnitus-specificdifferences in bimodal stimulus-timing dependent plasticity, we comparedresponses between Sham (n=100 units), ENT (n=63 units), and ET (n=225units) guinea pigs before and 15 minutes after bimodal stimulation ofvarying orders and intervals. Mean population timing rules for ET, ENT,and sham units revealed that bimodal plasticity was converted fromHebbian-like to anti-Hebbian-like timing rules in both the ET and ENTgroups (FIG. 14A). In the ET animals there were more bimodal intervalsat which enhancement occurred (−40, −20, −10, and 10 ms) than in the ENTgroup (only −20 ms), revealing a broadening of the timing rules for theenhancement phase of the curve in the ET animals. While firing ratesuppression was observed at +20 ms for both ET and ENT animals, therewas a broadening of the suppressive phase of the curve in the ENTanimals, with suppression at both +10 and +20 ms as compared to only +20ms in the ET animals (FIG. 14A). The broadening of the timing rules inthe enhancement phase in ET animals and in the suppressive phase in ENTanimals was in contrast to narrow, Hebbian-like timing rules in shamanimals, in which maximal enhancement and suppression were found atbimodal intervals of +20 ms and −10 ms respectively. A two-way ANOVAwith tinnitus group (TG) and bimodal interval (BI) revealed significantmain effects of tinnitus group and bimodal interval and a significantinteraction between bimodal interval and exposure group (TG−F(2)=4.02,p=0.018; BI−F(5)=4.72, p<0.001; TGxBI−F(10)=7.34, p<0.001). Bimodalintervals for which there were significant differences between tinnitusgroups according to Tukey-Kramer's post-hoc tests are shown as stars inFIG. 14A.

Corresponding with the shifts in population timing rules,anti-Hebbian-like units were most common in ET animals while suppressiveunits were predominant in ENT animals (FIG. 14B; Chi²=52.82; DF=11;p<0.001, stars in FIG. 14B). The shift towards anti-Hebbian-like unitsin ET animals was more prominent in units within the tinnitus frequencybands.

We also demonstrated that timing rules were broader and anti-Hebbian innoise-exposed animals. Above, we measured the stimulus-timing dependenceof bimodal plasticity to reveal the contribution of spike-timingdependent synaptic plasticity to bimodal plasticity. In these examples,we recorded responses from Sham (n=100 units), ENT (n=63 units), and ET(n=225 units) guinea pigs before, 3 and 15 minutes after bimodalstimulation with varying orders and intervals (FIG. 13A).

Mean population timing rules from all sham and noise-exposed units 3 and15 minutes after bimodal stimulation revealed that noise exposure shiftsthe population timing rule from Hebbian-like to anti-Hebbian-like innoise-exposed animals (FIG. 13B). In sham animals, both 3 and 15 minutesafter bimodal stimulation, the mean population timing rule wasHebbian-like, with enhancement of sound-evoked firing rates when Sp5preceded sound stimulation and suppression when Sp5 stimulation followedsound stimulation (FIG. 13B, labeled 302). In noise-exposed animals, thereverse occurred, with suppression of sound-evoked firing rates for Sp5preceding sound stimulation and enhancement with Sp5 following soundstimulation (FIG. 13B, labeled 306).

We also demonstrated that timing rules were broadest in noise-exposedanimals with tinnitus compared to those without tinnitus. Meanpopulation timing rules for ET, ENT, and sham units revealed thatlong-lasting bimodal plasticity 15 minutes after bimodal stimulation wasconverted from Hebbian-like to anti-Hebbian-like timing rules in boththe ET and ENT groups, but were broader in only the ET group (FIG. 13C).Additionally, in ENT animals, maximal enhancement and suppression werefound at bimodal intervals of −20 ms and +20 ms respectively, similar towhat was observed in sham guinea pigs with maximal enhancement andsuppression observed at 10 ms and −20 ms respectively. However, in ETanimals, maximal enhancement and suppression were observed at thebroadest bimodal intervals tested (+40 and −40 ms), suggesting thatbimodal plasticity timing rules broaden in association with tinnitus.

We found that anti-Hebbian bimodal plasticity was dominant in animalsexhibiting tinnitus, while suppressive bimodal plasticity was dominantin animals without tinnitus. Timing rules were constructed forindividual units from responses 15 minutes after bimodal stimulation andwere classified following the scheme previously described asHebbian-like (n=132), anti-Hebbian-like (n=69), suppressing (n=143), orenhancing (n=44) timing rules. Units from sham animals were distributedamong the timing rule classes similarly to units from normal animals butafter noise exposure, anti-Hebbian-like units were most common in ETanimals while suppressive units were predominant in ENT animals (FIG.14A). This corresponds with the shift in the population timing rule fromHebbian-like to anti-Hebbian-like (FIG. 13C).

Mean timing rules are shown for Hebbian, anti-Hebbian, and suppressiveunits from sham and ET animals in FIGS. 14B-G. Hebbian-like timing ruleswere similar and highly variable in both sham and ET animals (FIG.14B-C). Additionally, bimodal suppression was weaker in ET animals thanin sham animals (FIG. 14F-G).

We also found that anti-Hebbian bimodal plasticity of spontaneous rateswas dominant in noise-exposed guinea pigs exhibiting tinnitus, whilesuppressive bimodal plasticity of spontaneous rates was dominant inanimals without tinnitus. Tinnitus is associated with spontaneoushyperactivity in the DCN and other auditory structures. Spontaneousfiring rates measured before any bimodal stimulation revealed elevatedspontaneous firing rates in the ET group in frequency regions withthreshold shifts and evidence for tinnitus (below 12 kHz; FIGS. 15A and15B) but not above 12 kHz (FIGS. 15A and 15C). It is therefore importantto assess the influence of bimodal stimulation on subsequent spontaneousactivity in sham, ENT, and ET animals. FIG. 15D plots the change inspontaneous activity observed in DCN neurons 15 minutes after variousbimodal pairing orders and intervals in the three groups. These timingrules constructed from changes in spontaneous rates in units from ENTanimals were generally suppressive. In contrast, units from ET animalsexhibited anti-Hebbian-like timing rules with enhancement at the −20 msintervals and less suppression at all positive intervals than the ENTanimals. A two-way ANOVA with tinnitus group (TG) and bimodal interval(BI) revealed significant main effects of tinnitus group and asignificant interaction between bimodal interval and exposure group(TG−F(2)=14.06, p<0.0001; BI−F(5)=1.12, p=0.35; TGxBI−F(10)=2.41,p=0.008).

Further still, we demonstrated that exposed with tinnitus animals hadmore excitatory responses to Sp5 stimulation, over animals that were notexposed with tinnitus. Responses to Sp5 stimulation alone were recordedto identify whether the distribution of excitatory, inhibitory, andcomplex unimodal Sp5 responses differed with TTS-inducing noise exposureand with tinnitus (FIG. 16). Data plot 1 is the excitatory, unimodalresponse case. Data plot 2 is the mixed response case. Data plot 3 isthe inhibitory unimodal response case. Unimodal Sp5 responses were morelikely to be excitatory and less likely to be inhibitory in ET animalsthan in sham animals. In contrast, unimodal responses were more likelyto be complex (E/ln) in ENT animals.

Thus, as shown, to identify changes in stimulus-timing dependenceassociated with noise-exposure, bimodal plasticity timing rules werecompared between sham and all noise-exposed animals. We observed threesignificant noise-exposure associated changes: 1) timing rules were morelikely to be anti-Hebbian than Hebbian, 2) timing rules were broader,and 3) timing rules were more likely to be suppressive than enhancing.To identify changes specifically associated with noise-exposure inducedtinnitus, we compared timing rules from noise-exposed animals withtinnitus to timing rules from noise-exposed animals without tinnitus andsham animals. There were two striking differences in bimodal plasticityin tinnitus animals: 1) Timing rules were more likely to be governed byHebbian or anti-Hebbian timing rules than suppressive or enhancingtiming rules, and 2) Anti-Hebbian timing rules were broader. Theseresults likely represent underlying changes in STDP, suggesting apotential role for STDP in generating tinnitus.

The role of bimodal STDP in the DCN is to identify spatiotemporalpatterns in auditory nerve activity that are correlated withsomatosensory inputs. In a normal system, narrow STDP timing rulesheighten or suppress the responsivity of DCN neurons to auditory nerveinputs that are tightly correlated with somatosensory events. Thebroader timing rules in tinnitus animals would increase the likelihoodof a somatosensory event triggering anti-Hebbian or Hebbian plasticity,leading to heightened responsivity to spontaneous, as well as driven,auditory nerve spiking patterns. The resulting hyperactivity could be aneural representation of tinnitus. This mechanism could actcooperatively with the decreases in granule cell resistance observedafter noise exposure that further enhance the strength of somatosensoryinputs. Furthermore, the corresponding decrease in bimodal suppressionin tinnitus animals would further enhance the hyperactivity. Thetinnitus-associated changes in bimodal stimulus-timing dependentplasticity suggest that somatosensory inputs have a greater influence onDCN neural activity in animals that developed tinnitus than in thosethat did not.

We believe that noise-exposure and tinnitus are associated with STDPmetaplasticity that is likely driven by a combination of redistributionof somatosensory innervation and reduced influence of glycinergiccartwheel cells, cholinergic neuromodulation, and potentially changes inNMDAR and PKC-mediated signaling cascades.

Thus, these results confirm that metaplasticity of STDP in the DCN isnew neural correlate of tinnitus. The specific combination of STDPchanges in DCN after noise exposure may drive spontaneous neuralactivity toward spiking patterns that represent tinnitus in DCN andhigher auditory structures in the auditory system. The influence ofmetaplasticity in higher centers could further drive spontaneousactivity towards perceptual awareness. In the end, these experimentsfurther demonstrate the particular and unexpected advantages of thistechnique in the treatment of tinnitus.

The experimental procedures used for a second set of example testingprocedures, corresponding to FIGS. 9-16, were as follows. Animals:Female pigmented guinea pigs (n=16) from the Elm Hill colony (300-400 g;Ann Arbor, Mich.) were used in this study. Experimental design: Thisstudy was designed to assess the effect of noise-exposure inducedtinnitus on stimulus-timing dependent bimodal plasticity of sound-evokedresponses and spontaneous activity. Sixteen female guinea pigs (ElmHill, 10 noise-exposed and 6 sham-exposed) were behaviorally testedsemiweekly before and after a two hour noise exposure (FIG. 9, plot “A”:97 dB noise with ¼ octave band centered at 7 kHz) using an acousticstartle-based gap detection assay for tinnitus (FIG. 9, plot “B”). Tenguinea pigs were first exposed to the narrowband noise 3-6 weeks afterbaseline gap detection testing. Six to 8 weeks later, each guinea pigwas exposed a second time to the same narrowband noise. The remaining 6guinea pigs were sham-exposed at the same time. Auditory brainstemresponse (ABR) thresholds were measured before beginning gap detection(B), immediately after the first and second noise exposures to assessthreshold shift (E1 & E2), one week after each noise exposure to assessrecovery of thresholds (R1 & R2), and immediately before unit recordings(F; FIG. 9, plot “C”). Four to six weeks after the 2nd noise exposure,single and multi-unit spontaneous activity, rate level functions, andbimodal stimulus-timing dependent plasticity were assessed in an acuteDCN recording preparation and compared between sham and exposed groupsand between tinnitus and no tinnitus groups (FIG. 9, plot “D”).

Gap detection testing for tinnitus: Guinea pigs were behaviorally testedwith a startle-based gap detection assay for tinnitus two times per weekfollowing the previously described protocol (Dehmel et al., 2012b). Inbrief, guinea pigs were placed on top of a piezoelectric forcemeasurement plate to measure movement elicited by a loud broadband noise(the startle stimulus; 115 dB, 200-20 kHz). Each trial consisted of abackground noise with (Gap trials) or without (No-Gap trials) a 50 mssilent gap embedded 50 ms before the startle stimulus onset. The 60 dBbackground noise was either broad band noise or bandpass filtered noisewith a 2 kHz band and lower cutoff frequencies of 4, 8, 12, 16, or 20kHz. Intervals between trials randomly varied between 18 and 24 seconds.For each day of testing, an observation of the normalized startleresponse was computed as the ratio [A_(G)/A_(NG)], where A_(G) is themean amplitude of the startle responses from 10 trials with gap on oneday and A_(NG) is the mean amplitude of the startle response from 10trials with no gap on the same day (FIG. 10A). To assess the normalizedstartle responses within each frequency band for evidence of tinnitusfor each frequency band (12 KHz is shown), the distribution ofnormalized startle trials from all observations from all animals wasanalyzed using Gaussian mixture modeling (Statistics Toolbox, Matlabrelease 2012b) assuming that the normalized startle observations weredrawn from one of two distributions, the normal distribution (FIG. 10B,402) and the tinnitus distribution (FIG. 10B, 404). The normalizedstartle observations were placed into the tinnitus group when theposterior probability was greater than 0.55 (FIG. 10C, 406). For eachfrequency band, using the threshold established by the Gaussian mixturemodel, the distributions of normalized startle responses from shamanimals after noise exposure (Sham, FIG. 10D), all animals before noiseexposure (Baseline, FIG. 10E), and exposed animals after noise exposure(Exposed, FIG. 10F) were partitioned into tinnitus and no tinnitusobservations. Animals from the exposed group that demonstrated moretinnitus observations than were found during baseline testing wereconsidered to have tinnitus within the tested frequency band. For FIGS.10D-10F only the distribution 402 is labeled, corresponding tonon-tinnitus; the other distribution values correspond to distribution404, corresponding to tinnitus. For statistical evaluation, animals withno exposure were assigned to the sham group, noise-exposed animals withno evidence for tinnitus were assigned to the Exposed-No-Tinnitus (ENT)group, and noise-exposed animals with evidence for tinnitus wereassigned to the Exposed-Tinnitus (ET) group. Pre-pulse inhibition wasassessed in the same manner as gap-detection. All groups of animalsshowed no differences in pre-pulse inhibition before and after the noisedamage. This result was taken to mean that baseline temporal processingwas unchanged by the noise damage and therefore any changes ingap-detection were as a result of the tinnitus “filling the gap” and notbecause of a temporal processing dysfunction or hearing loss.

Surgical approach for neural recordings: Guinea pigs were anesthetized(subcutaneous injection of ketamine and xylazine, 40 mg/kg, 10 mg/kg; atthe incision site a subcutaneous injection of lidocaine, 4 mg/kg) andophthalmic ointment applied to their eyes. Their heads were fixed in astereotaxic frame using a bite bar and hollow ear bars were placed intothe ear canals. Core temperature was maintained at 38° C. A leftcraniotomy was performed and a small amount of cerebellum was aspirated(leaving paraflocculus intact) to allow for visual placement of therecording electrode. Supplemental doses of ketamine and xylazine (I.M.)were administered at least hourly when indicated by response to a toepinch. The guinea pig's physiological condition was monitored byassessment of body temperature, respiration and heart rates, and unitthresholds. After the completion of neural recording, the guinea pig wassacrificed by I.P. injection of sodium pentobarbitol followed bydecapitation.

Electrode placement: A concentric bipolar stimulating electrode (FHC,Bowdoin, Me.) was placed stereotaxically into Sp5 after being dipped influorogold; −10 degrees below horizontal, 0.28+/−0.03 cm lateral frommidline; 0.25+/−0.02 cm caudal from transverse sinus; 0.9+/−0.1 cm belowsurface of cerebellum. Post-mortem reconstruction confirmed electrodelocations. A four-shank, thirty two-channel silicon-substrate electrode(site spacing=100 um, shank pitch=250 um, site area=177 um2,impedance=1-3 mOhms, Neuro Nexus, Ann Arbor, Mich.) was placed with thetips 0.8-1.0 um below the surface of the DCN with shanksrostral-to-caudal approximately within an iso-frequency layer. If thetop site on each shank did not respond to sound, the electrode waslowered until they responded to noise.

Auditory and somatosensory stimulation: Cosine window-gated Tone signals(50 ms duration, 2 ms rise/fall time) were generated using Open Ex andan RX8 DSP (TDT, Alachula, Fla.) with 12 bit precision and samplingfrequency set at 100 kHz. A shielded speaker (DT770, Beyer) driven by anHB7 amplifier (TDT, Alachula, Fla.) delivered sound through a hollowearbar to the left ear. The system response was measured using acondenser microphone attached to the hollow earbar by a ¼″ long tubeapproximating the ear canal. Sound levels were adjusted to account forthe system response using a programmable attenuator (PA5, TDT, Alachula,Fla.) to deliver calibrated levels (dB SPL) at frequencies from 200 Hzto 24 kHz. Neurons in somatosensory brainstem nuclei known to project toDCN were activated by three biphasic (100 us/phase) current pulses at1000 Hz delivered to Sp5 through a concentric bipolar electrode. Thecurrent amplitude was set to the highest level (range: 50-70 μA) thatdid not elicit movement artifact.

Assessment of stimulus-timing dependent bimodal plasticity:Stimulus-timing dependent plasticity was assessed in all guinea pigsusing an established in vivo bimodal plasticity induction protocol. Inshort, spontaneous activity and responses to unimodal tone stimuli wererecorded at three time points: before, and 3 and 15 minutes after thebimodal stimulation protocol. The bimodal stimulation protocol in thisexample consisted of 300 trials of the 50 ms tones combined with Sp5activation. The bimodal interval was defined as the Sp5 stimulus onsettime minus the tone stimulus onset time. Thus, positive bimodalintervals indicate Sp5-leading tone stimulation and negative bimodalintervals indicate tone-leading Sp5 stimulation. Stimulus-timingdependence was assessed by varying the bimodal interval and measuringthe change in unimodal tone-evoked firing rates before and after bimodalstimulation. The recording block was repeated with the bimodal intervalbetween tone and somatosensory stimuli randomly selected from thefollowing list: −40, −20, −10, 0, 10, 20, or 40 ms. Control recordingblocks were also included in which unimodal tone or Sp5 stimuli replacedthe bimodal stimuli. To assess recovery after bimodal stimulation,responses to unimodal tones were measured every 15-30 minutes for aslong as possible to assess recovery after bimodal stimulation.

To assess recovery after bimodal stimulation, responses to unimodaltones were measured every 15-30 minutes after the final bimodalstimulation block for up to 2 hours. Timing rules for principal cellunits (excluding units with type II receptive fields) were classified asHebbian, anti-Hebbian, suppressing, or enhancing by comparing the meanchange in firing rate (i.e., the firing rate before bimodal stimulationsubtracted from the firing rate after bimodal pairing) when the Sp5stimulus preceded the sound and when the Sp5 stimulus followed thesound. Timing rule classification corresponded to that used previously.For comparison between sham, ET, and ENT animals, spontaneous firingrates were measured from the first recording block before any bimodalstimulation.

Spike detection and sorting: Voltages from each site were digitized by aPZ2 preamp (Fs=12 kHz, TDT, Alachua, Fla., USA) and band-pass filtered(300 Hz-3 kHz). Online spike detection used a voltage threshold set 2.5standard deviations above background noise (RZ2, TDT, Alachua, Fla.,USA). Timestamps and waveform snippets were saved to a PC and sortedusing principal components of the waveform shape and K-means clusteranalysis with fixed variance (95%) and 5 clusters (Plexon OfflineSorter). Cluster distinctness was confirmed with pairwise clusterstatistics (p>0.05; Plexon Offline Sorter) and visually by a trainedobserver. When a spike was present in a 1 ms window across 80% ofchannels, any spikes within that window were considered artifact andremoved from further analysis. The waveform shapes, amplitudes, andresponse properties of multi-unit clusters in this study were consistentover the duration of the recording.

As discussed herein, the techniques may apply the auditory component ofbimodal stimulation at frequencies identified as tinnitus frequencies orat other frequencies determined to reduce tinnitus. In further examples,the techniques may present timing intervals at, for example, +10 ms or+20 ms (i.e., somatosensory stimulation before auditory stimulation) atthe tinnitus frequency, while timing intervals at, for example, −10 msand −20 ms (i.e., auditory stimulation before somatosensory stimulation)for ‘off-tinnitus’ frequencies. This will have the effect of reducinghyperactivity seen at the tinnitus frequency regions of the cochlearnucleus and increasing activity in regions not associated with tinnitus,thus ‘equalizing’ the firing rates across all frequencies. Furtherstill, in some examples, the treatment techniques herein may present astatistical distribution of bimodal intervals. For example, the tinnitusfrequency could be paired with somatosensory stimulation at intervalspulled from a Gaussian distribution centered at −15 ms with a standarddeviation of 2 ms. Non-tinnitus frequencies could be either paired atintervals pulled from a broad Gaussian or uniform distribution centeredat 0 ms or could be paired at intervals pulled from a Gaussiandistribution centered at +15 ms with a standard deviation of 2 ms.Having varied bimodal intervals, for example, over a statisticaldistribution, a few features may result. It may allow for fine tuningany initial bimodal interval, which may be useful for initial intervalsthat are estimates. Moreover, neurons may have varied preferred timingsfor suppression. Therefore, by varying the bimodal interval, ondifferent trials, the techniques may more readily achieve the maximalsuppression for some neurons and partial suppression for others. Furtherstill, by applying a distribution of bimodal treatments, one can addressthe possibility that preferred intervals will drift over time with thestate of the auditory system.

FIGS. 17A and 17B illustrate an example hardware system and softwarediagram as may be used for implementing the tinnitus reductiontechniques described herein. FIG. 17A illustrates a bimodal stimulationmachine 900 having a processing unit 902 and memory 903 that executesinstructions providing a user interface 904 to a user, for examplethrough a display screen and that interfaces with a computer 906 thatmay provide instructions to the machine 900 for performing bimodalstimulation of a patient. As discussed in examples herein, the computer906 may perform signal and data analysis to determine timing controls,e.g., determining the order, spacing, frequency, amplitudes, etc. fortwo stimulation signals, an auditory stimulation signal and asomatosensory stimulation signal, transmitted via an audio signalgenerator 908 and an electrical signal generator 910 in the illustratedexample of FIG. 17A. While various features are described as performedby one or both of the machine 900 and the computer 906, it will beunderstand that any of the features described herein may be performedone or both of these, and that either individually or collected may bereferred to herein as an example bimodal stimulation system, of whichother examples are also provided herein, including in FIG. 18.

FIG. 17B illustrates a software platform 950 that may be executed byinstruction on the machine 900, the computer 906, or some combinationthereof, in various example implementations of the present techniques. Astartup mode 952 initiates operation through a boot process 954, fromwhich the machine 900 enters into an input mode 956. From the input mode956, the machine 900 determines, at a decision block 958, whether themachine is to be in the input mode 956 or a protocol mode (also termed atreatment mode) 960, e.g., as may be selected by a user. An optionalblock 957 is shown a represents a user input waiting call instructionwith a five minute limit before initiating system shutdown 959. In inputmode 956, the platform 950 determines, at block 962, whether the userinterface is on or not, where if it is not already one, then it isturned on at block 964. Either way, control is provide to an inputawaiting block 966, which awaits input from the user via block 968 andmore specifically may request from the use whether the user wants to runa trial bimodal stimulation procedure. If so, a user inputs a request atblock 969 before passing control back to the block 966 and on to aprotocol switching mode initiator 970. Otherwise the block 968 passescontrol to shutdown procedure 959.

Once, at block 958, a protocol mode exists, control is passed to theprotocol model 960, and more specifically to an update parameters block972 that determines the parameters for bimodal stimulation, includingthe order, spacing, frequency, amplitudes, of the auditory system andsomatosensory system stimulation signals. In some examples, theseparameters may be retrieved from a historical data of past treatmentparameters. In some examples, these parameters may be prognosticallydetermined from current and/or historical patient data, such asphysiological data measured for a patient. In some examples, theseparameters may be determined from patient input. For example, with themachine 900 implemented as point of care computer, such as a laptop,tablet computer, mobile smart phone, netbook, notebook computer,personal data assistant, handheld device, or desktop device, a user maybe presented with a user interface that allows them to select theparameters for both the auditory system and somatosensory systemstimulation signals, until the tinnitus or hyperacusis, etc. has beensufficiently treated. As such as smart device, the machine 900 mayrecord the parameters as the user is identifying the optimum parametersettings for treatment, including recording the time and day of thetreatment. In some examples, the smart device also automaticallydetermines an optimum adjustment scale, selectively determining overwhich parameter ranges to apply a course tunability adjustment scale ofthe parameter value versus over which parameter ranges to apply a finetunability adjustment scale. In this way, the smart device may allow apatient to do course adjustments on parameters, until those parametervalues approach a predicted range, from which the smart device mayswitch to a fine adjustment scale to allow a patient better control indetermining the exact parameters.

In any event, in the illustrated example, the block 972 updates theparameters for bimodal stimulation from stored data; and theseparameters are sent to hardware such as to the signal generators (e.g.,transducers) 908 and 910 through a block 974 and the bimodal stimulationtreatment is provided to the patient. The treatment may be for adetermined or predetermined period of time. Therefore, in some examples,a control loop is used to successively apply the bimodal stimulationtreatment for the desired time period until it is determined at theblock 976 that the treatment protocol is finished. The treatmentduration may be automatically determined by the system, may be set bythe patient or health care provider, may be determined from historicaldata on the patient, or may be determined from historical data across anidentified patient population. These are provided by way of example.When the protocol mode set is finished (as determined at block 976) themode is switched to an input mode, via a block 978. A user may modulatevarious parameters to affect the timing between an auditory systemstimulus and a somatosensory system stimulus, such as repetition count,and stimulus parameters such as intensity, frequency, time separation,time delay, and duration, where such control may be achieved over amillisecond or smaller time control, in some examples.

FIG. 18 illustrates an exemplary bimodal stimulation system forimplementing the blocks of the method and apparatus includes ageneral-purpose computing device in the form of a computer 12.Components of computer 12 may include, but are not limited to, aprocessing unit 14 and a system memory 16. The computer 12 may operatein a networked environment using logical connections to one or moreremote computers, such as remote computers 70-1, 70-2, . . . 70-n, via alocal area network (LAN) 72 and/or a wide area network (WAN) 73 via amodem or other network interface 75. These remote computers 70 mayinclude other computers like computer 12, but in some examples, theseremote computers 70 include one or more of (i) an auditory stimulationmachine, (ii) a somatosensory stimulation machine, (iii) a signalrecords database systems, (iv) a scanner, and/or (v) a signal filteringsystem.

In the illustrated example, the computer 12 is connected to a bimodalstimulation machine, labeled machine 70-1. The bimodal stimulationmachine 70-1 may be a stand-alone system, having multiple stimulationleads for transmitting bimodal stimulation signals in accordance withthe techniques described herein. In other examples, a series ofstimulation probes may be connected directly to the computer 12.

Computer 12 typically includes a variety of computer readable media thatmay be any available media that may be accessed by computer 12 andincludes both volatile and nonvolatile media, removable andnon-removable media. The system memory 16 includes computer storagemedia in the form of volatile and/or nonvolatile memory such as readonly memory (ROM) and random access memory (RAM). The ROM may include abasic input/output system (BIOS). RAM typically contains data and/orprogram modules that include operating system 20, application programs22, other program modules 24, and program data 26. For example, thetinnitus detection, bimodal stimulation analysis, and bimodalstimulation treatment techniques described herein may be implemented asinstructions stored in the application programs block 22 and executableby computer 12. The computer 12 may also include otherremovable/non-removable, volatile/nonvolatile computer storage mediasuch as a hard disk drive, a magnetic disk drive that reads from orwrites to a magnetic disk, and an optical disk drive that reads from orwrites to an optical disk.

A user may enter commands and information into the computer 12 throughinput devices such as a keyboard 30 and pointing device 32, commonlyreferred to as a mouse, trackball or touch pad. Other input devices (notillustrated) may include a microphone, joystick, game pad, satellitedish, scanner, or the like. These and other input devices are oftenconnected to the processing unit 14 through a user input interface 35that is coupled to a system bus, but may be connected by other interfaceand bus structures, such as a parallel port, game port or a universalserial bus (USB). A monitor 40 or other type of display device may alsobe connected to the processor 14 via an interface, such as a videointerface 42. In addition to the monitor, computers may also includeother peripheral output devices such as speakers 50 and printer 52,which may be connected through an output peripheral interface 55.

Generally, the techniques herein may be coded any computing language forexecution on computer 12. Stimulation instruction data may be determinedat the remote computers 70-1, 70-2, . . . 70-n or at any of the computerstorage devices of computer 12. The instructions may be stored on any ofthese computers and devices as well. Furthermore, the remote computers70-1, 70-2, . . . 70-n may receive instructions from a patientindicating perceived effectiveness the bimodal stimulation, for thecomputer 12 or the remote computers to adjust the stimulation controlsignals in response thereto.

A user may input or select the condition parameters through an inputmechanism to set the applied bimodal stimulation. Although, in otherexamples, the parameters for bimodal stimulation may be pre-selected orautomatically determined, for example, based on a particular type ofanalysis that is to be performed. The output of the executable programmay be displayed on a display (e.g., a monitor 40), sent to a printer52, stored for later use by the computer 12, or offloaded to anothersystem, such as one of the remote computers 70. The output may be in theform of an image (such as the figures herein), a graph, a table or anycombination thereof, by way of example. Operations of the system may berecorded in a log database for future reference as shown. This logdatabase may be accessed at subsequent times.

With the systems described, by way of example herein (e.g., FIGS. 17A,17B, and 18), techniques to treat tinnitus may be achieved. Further, itwill be appreciated that examples described herein as achieved by any ofthe machines and/or software of these figures, may be achieved by anyother of these machines and/or software, as well as by other systems.These techniques include generating an audible stimulation signal (e.g.,a pure tone, a narrowband noise, a broadband noise, a harmonic complex,etc., or some combination thereof) having a first firing point and firstfiring period, stimulus onset, and/or duration. They may also includegenerating a somatosensory stimulation signal to stimulate asomatosensory system of a subject, the somatosensory stimulation signalhaving a second firing point and second firing period, stimulus onset,and/or duration. A timing order and timing difference between the firstfiring point and the second firing point may then be established toreduce the tinnitus. The first firing period and the second firingperiod may be maintained asynchronously to reduce tinnitus so that theonset of the first firing period does not overlap the onset of thesecond firing period. In some examples, the entire first and secondfiring periods do not overlap. In some examples, the first firing pointwill be before the second firing point, while in other examples, thefiring point order will be reversed. The timing order may be changed todetermine a desired reduction or illumination in tinnitus, for example,based on responses of subject.

The bimodal stimulation machine 70-1, for example, may be controlled toestablish first and second firing conditions (e.g., firing points,firing periods, duration, stimulation signal pattern for both electricaland auditory signals, stimulation signal intensities) to reduce orremove tinnitus. In some examples, the machine 70-1 may include probespositioned to apply, to a subject, a somatosensory stimulation signal byapplying stimulation to the brain to stimulate the somatosensory system.In some examples, the machine 70-1 may include probes that applying thesomatosensory stimulation signal to the subject by applying stimulationto the trigeminal nerve via facial stimulation or the cervical spinalnerve of the subject to stimulate the somatosensory system. In someexamples, the probes are deep brain region probes that stimulate thesomatosensory system. Thus in some examples, the somatosensorystimulation signal to a subject results from applying stimulation to asurface region of the brain of the subject or to a surface structure onthe face or a surface structure on the neck of the subject to stimulatethe somatosensory system. These stimulations, whether auditorystimulation and somatosensory stimulation, may be provided through amechanical or electrical stimulation.

In addition to applying the bimodal stimulation, the systems describedmay be used to determine a timing profile for a subject. The timingprofile may contain timing data of different timing orders and timingdifferences between the first firing point and the second firing pointand containing perceived tinnitus data for the different timing ordersand timing differences. That data may be stored in the memory 16, forexample, as timing profile data, which may be later used by the machine12 to determine a suggested tinnitus treatment regimen for bimodalstimulation using the auditory stimulation signal and the somatosensorystimulation signal.

For example, different timing orders may be provided to a subjectthrough the stimulation machine 70-1, while the subject responds, usingthe machine 70-1 (or other input device or verbally to a practitionerusing the machine 12) with a perceived reduction in tinnitus. Thatperception data is recorded by the machine 12 along with the bimodalstimulation conditions to develop a timing profile for how to reducetinnitus experienced by that particular subject. That profile may bedeveloped over numerous tests, i.e., based on historically collecteddata for the patient.

Using this timing profile, the machine 12 can, in some examples,determine an initial timing profile for a subject, the timing profilecontaining an initial timing order and timing difference for the firstfiring point and the second firing point. The timing profile has beendetermined to reduce tinnitus after onset.

In this way the systems described herein can automatically establish atiming order and timing difference between first and second firingpoints to reduce tinnitus.

In some examples, the timing profile may be developed to include globaltime data, so that the timing profile includes project times of day,days in the week, etc. when tinnitus seems to occur more frequency forthe patient. The machine 12 may use the timing profile to attempt topre-empt onsets of tinnitus based on this timing profile example.

Thus, the machine 12 may adjust the timing order and timing differencebetween firing points to determine a tinnitus reduction profile for aperiod of time, where this profile may be accessed later for applyingbimodal stimulation. For example, when a treatment time is identified(e.g., a future point in time or from an trigger such as subjectactivating the bimodal stimulation treatment upon perceiving tinnitus),this profile may be accessed to identify a timing order and timingdifference for the treatment time, which may then be applied using thestimulation machine 70-1. In some examples, the machine 12 mayperiodically adjust the first and/or second firing periods to affecttinnitus reduction. In any event, as will be appreciated by theforegoing adjusting the timing order and the timing difference betweenthe first firing point and the second firing point to selectivelyincrease or decrease firing rates in an identified neurons.

While example implementations are described for treating tinnitus, thepresent techniques are not limited to the treatment of tinnitus. Thetechniques may be used to treat any number of auditory conditions, ofwhich hyperacusis is an example. Moreover the application programs 22may include other instructions for treating an auditory condition. Theseinclude: instructions for increasing firing rates for the neurons in thedorsal cochlear nucleus, ventral cochlear nucleus, and/or auditorycortex; instructions for decreasing firing rates for the neurons in thedorsal cochlear nucleus, ventral cochlear nucleus, inferior colliculus,auditory cortex and/or other nuclei associated with tinnitus.

In some examples, the computer 12 determines optimal parameter valuesfor an audible stimulation signal and a somatosensory stimulation signalto alter firing rates for neurons in the dorsal cochlear nucleus,ventral cochlear nucleus, and/or auditory cortex.

In some examples, the computer 12 identifies initial parameters fortiming and intervals of a bimodal stimulation for a subject byidentifying stimulation parameters that in the subject produce areduction in objective measures of neural correlates of tinnitusassessed by any of an electroencephalography test, auditory brainstemresponse (ABR) test, or psychophysical tinnitus matching test.

It will be appreciated that the techniques may be used to treat anynumber of auditory diseases, using targeted neural suppression orenhancement via specifically-timed auditory-somatosensory stimulation.These include cochlear implants and central auditory processingdisorder. For cochlear implants, tonotopic remapping after implantationoccurs gradually and likely plays a role in implant training. Duringtraining, cochlear implant stimulation followed by somatosensorystimulation would lead to enhanced responses, potentially acceleratingtonotopic remapping. For auditory processing disorders, complex soundsthat are poorly distinguished could be presented followed bysomatosensory stimulation, leading to enhanced responses to thosecomplex sounds, and better neural representation.

It will be appreciated that the above descriptions are provided by wayof example and that numerous modifications may be made within context ofthe present techniques.

More generally, the various blocks, operations, and techniques describedabove may be implemented in hardware, firmware, software, or anycombination of hardware, firmware, and/or software. When implemented inhardware, some or all of the blocks, operations, techniques, etc. may beimplemented in, for example, a custom integrated circuit (IC), anapplication specific integrated circuit (ASIC), a field programmablelogic array (FPGA), a programmable logic array (PLA), etc.

When implemented in software, the software may be stored in any computerreadable memory such as on a magnetic disk, an optical disk, or otherstorage medium, in a RAM or ROM or flash memory of a computer,processor, hard disk drive, optical disk drive, tape drive, etc.Likewise, the software may be delivered to a user or a system via anyknown or desired delivery method including, for example, on a computerreadable disk or other transportable computer storage mechanism or viacommunication media. Communication media typically embodies computerreadable instructions, data structures, program modules or other data ina modulated data signal such as a carrier wave or other transportmechanism. The term “modulated data signal” means a signal that has oneor more of its characteristics set or changed in such a manner as toencode information in the signal. By way of example, and not limitation,communication media includes wired media such as a wired network ordirect-wired connection, and wireless media such as acoustic, radiofrequency, infrared and other wireless media. Thus, the software may bedelivered to a user or a system via a communication channel such as atelephone line, a DSL line, a cable television line, a wirelesscommunication channel, the Internet, etc. (which are viewed as being thesame as or interchangeable with providing such software via atransportable storage medium).

Moreover, while the present invention has been described with referenceto specific examples, which are intended to be illustrative only and notto be limiting of the invention, it will be apparent to those ofordinary skill in the art that changes, additions and/or deletions maybe made to the disclosed embodiments without departing from the spiritand scope of the invention.

Thus, although certain apparatus constructed in accordance with theteachings of the invention have been described herein, the scope ofcoverage of this patent is not limited thereto. On the contrary, thispatent covers all embodiments of the teachings of the invention fairlyfalling within the scope of the appended claims either literally orunder the doctrine of equivalents.

What is claimed is:
 1. A computer-implementable method of treatingtinnitus in a subject, the method comprising: generating, in an audiblesignal generator, an audible stimulation signal having a first firingpoint and first firing period, stimulus onset, and/or duration;generating, in an electrical signal generator, a somatosensorystimulation signal to stimulate a somatosensory system of a subject, thesomatosensory stimulation signal having a second firing point and secondfiring period, stimulus onset, and/or duration; and establishing, in aprocessor coupled to the audible signal generator and the electricalsignal generator, a timing order and timing difference between the firstfiring point and the second firing point to reduce the tinnitus, whereinthe first firing period and the second firing period are to bemaintained asynchronously to reduce the tinnitus so that the firingperiod does not overlap the second firing period; and applying thesomatosensory stimulation signal to the somatosensory system of thesubject, and applying the audible stimulation signal to an auditorysystem of the subject.
 2. The method of claim 1, further comprisingchanging the timing order between the first firing point and the secondfiring point to determine a desired reduction in the tinnitus.
 3. Themethod of claim 1, further comprising adjusting the timing differencebetween the first firing point and the second firing point to determinea desired reduction in the tinnitus.
 4. The method of claim 1, furthercomprising applying the somatosensory stimulation signal to the subjectby applying stimulation to a brain of the subject to stimulate thesomatosensory system.
 5. The method of claim 4, further comprisingapplying the somatosensory stimulation signal to the subject by applyingstimulation to a trigeminal nerve of the subject via facial stimulationor a cervical spinal nerve of the subject to stimulate the somatosensorysystem.
 6. The method of claim 4, further comprising applying thesomatosensory stimulation signal to the subject by applying stimulationto a deep brain region of the subject to stimulate the somatosensorysystem.
 7. The method of claim 4, further comprising applying thesomatosensory stimulation signal to the subject by applying stimulationto a surface region of a brain of the subject or to a surface structureon a face or a surface structure on a neck of the subject to stimulatethe somatosensory system.
 8. The method of claim 1, wherein at least oneof the auditory stimulation signal and the somatosensory stimulationsignal is provided to the subject through mechanical or electricalstimulation.
 9. The method of claim 1, further comprising: determining atiming profile for the subject, the timing profile containing timingdata of different timing orders and timing differences between the firstfiring point and the second firing point and containing perceivedtinnitus data for the different timing orders and timing differences;and storing the timing profile for access in determining a suggestedtinnitus treatment regimen for the auditory stimulation signal and thesomatosensory stimulation signal.
 10. The method of claim 1, furthercomprising: determining an initial timing profile for the subject, thetiming profile containing an initial timing order and timing differencefor the first firing point and the second firing point, and determinedto reduce the tinnitus after onset.
 11. The method of claim 1, furthercomprising: receiving an indication of the onset of the tinnitus; andautomatically establishing the timing order and the timing differencebetween the first firing point and the second firing point to reduce thetinnitus.
 12. The method of claim 1, further comprising: adjusting, overa period of time, the timing order and the timing difference between thefirst firing point and the second firing point to determine a tinnitusreduction profile for the period of time; and storing the tinnitusreduction profile.
 13. The method of claim 12, wherein establishing thetiming order and the timing difference between the first firing pointand the second firing point comprises: accessing the tinnitus reductionprofile; and determining the timing order and the timing difference fromthe tinnitus reduction profile.
 14. The method of claim 12, whereinestablishing the timing order and the timing difference between thefirst firing point and the second firing point comprises: identifying atreatment time; accessing the tinnitus reduction profile; identifyingthe timing order and the timing difference corresponding to thetreatment time from the tinnitus reduction profile; and applying thegenerated auditory stimulation signal and somatosensory stimulationsignal based on the identified corresponding timing order and timingdifference.
 15. The method of claim 12, wherein the identified treatmenttime is a present time.
 16. The method of claim 12, wherein theidentified treatment time is a future time.
 17. The method of claim 1,further comprising: adjusting the first firing period and/or the secondfiring period to reduce the tinnitus.
 18. The method of claim 1, furthercomprising: periodically adjusting the first firing period and/or thesecond firing period to reduce the tinnitus.
 19. The method of claim 1,further comprising: adjusting the timing order and the timing differencebetween the first firing point and the second firing point toselectively increase or decrease firing rates in an identified neurons.20. A system for treating an auditory condition in a subject, the systembeing capable of stimulating (i) a somatosensory system of the subjectwith a generated somatosensory stimulation signal and (ii) an auditorysystem of the subject with an audible stimulation signal, the systemcomprising: a bimodal stimulation system having an audible signalgenerator, a somatosensory signal generator, a processor, and a memory,wherein the processor is operatively coupled to the audible signalgenerator and the somatosensory signal generator to control each, andwherein the bimodal stimulation system is configured to, generate, inthe audible signal generator, the audible stimulation signal having afirst firing point and first firing period, stimulus onset, and/orduration, and generate, in the somatosensory signal generator, thesomatosensory stimulation signal to stimulate a somatosensory system ofa subject, the somatosensory stimulation signal having a second firingpoint and second firing period, stimulus onset, and/or duration, whereinthe memory stores instructions that when executed by the processor causethe processor to: establish a timing order and timing difference betweenthe first firing point and the second firing point to reduce theauditory condition, wherein the first firing period and the secondfiring period are to be maintained asynchronously to reduce the auditorycondition so that the onset of the first firing period does not overlapthe onset of the second firing period.
 21. The system of claim 20,wherein the bimodal stimulation system is further configured to changethe timing order between the first firing point and the second firingpoint to determine a desired reduction in the auditory condition. 22.The system of claim 20, wherein the bimodal stimulation system isfurther configured to adjust the timing difference between the firstfiring point and the second firing point to determine a desiredreduction in the auditory condition.
 23. The system of claim 20, whereinthe bimodal stimulation system is further configured to apply thesomatosensory stimulation signal to the subject by applying stimulationto a brain of the subject through one or more electrodes to stimulatethe somatosensory system.
 24. The system of claim 23, wherein thebimodal stimulation system is further configured to apply thesomatosensory stimulation signal to the subject by applying stimulationto a trigeminal nerve of the subject via facial stimulation through oneor more electrodes or a cervical spinal nerve of the subject through oneor more electrodes to stimulate the somatosensory system.
 25. The systemof claim 23, wherein the bimodal stimulation system is furtherconfigured to apply the somatosensory stimulation signal to the subjectby applying stimulation to a deep brain region of the subject throughone or more electrodes to stimulate the somatosensory system.
 26. Thesystem of claim 23, wherein the bimodal stimulation system is furtherconfigured to apply the somatosensory stimulation signal to the subjectby applying stimulation to a surface region of a brain of the subjectthrough one or more electrodes or to a surface structure on a face or asurface structure on a neck of the subject through one or moreelectrodes to stimulate the somatosensory system.
 27. The system ofclaim 20, wherein at least one of the auditory stimulation signal andthe somatosensory stimulation signal is provided to the subject througha mechanical or electrical stimulation.
 28. The system of claim 20,wherein the bimodal stimulation system is further configured to:determine a timing profile for the subject, the timing profilecontaining timing data of different timing orders and timing differencesbetween the first firing point and the second firing point andcontaining perceived auditory condition data for the different timingorders and timing differences; and store the timing profile for accessin determining a suggested auditory condition treatment regimen for theauditory stimulation signal and the somatosensory stimulation signal.29. The system of claim 20, wherein the bimodal stimulation system isfurther configured to: determine an initial timing profile for thesubject, the timing profile containing an initial timing order andtiming difference for the first firing point and the second firingpoint, and determined to reduce the auditory condition after onset. 30.The system of claim 20, wherein the bimodal stimulation system isfurther configured to: receive an indication of the onset of theauditory condition; and automatically establish the timing order and thetiming difference between the first firing point and the second firingpoint to reduce the auditory condition.
 31. The system of claim 20,wherein the bimodal stimulation system is further configured to: adjust,over a period of time, the timing order and the timing differencebetween the first firing point and the second firing point to determinean auditory condition reduction profile for the period of time; andstore the auditory condition reduction profile.
 32. The system of claim20, wherein the bimodal stimulation system is further configured toestablish the timing order and the timing difference between the firstfiring point and the second firing point by: accessing an auditorycondition reduction profile; and determining the timing order and thetiming difference from the auditory condition reduction profile.
 33. Thesystem of claim 20, wherein the bimodal stimulation system is furtherconfigured to establish the timing order and the timing differencebetween the first firing point and the second firing point by:identifying a treatment time; accessing an auditory condition reductionprofile; identifying the timing order and the timing differencecorresponding to the treatment time from the auditory conditionreduction profile; and applying the generated auditory stimulationsignal and somatosensory stimulation signal based on the identifiedcorresponding timing order and timing difference.
 34. The system ofclaim 33, wherein the identified treatment time is a present time. 35.The system of claim 33, wherein the identified treatment time is afuture time.
 36. The system of claim 20, wherein the bimodal stimulationsystem is further configured to adjust the first firing period and/orthe second firing period to reduce the auditory condition.
 37. Thesystem of claim 20, wherein the bimodal stimulation system is furtherconfigured to periodically adjust the first firing period and/or thesecond firing period to reduce the auditory condition.
 38. The system ofclaim 20, wherein the bimodal stimulation system is further configuredto adjust the timing order and the timing difference between the firstfiring point and the second firing point to selectively increase ordecrease firing rates in an identified neurons.
 39. The system of claim20, wherein the auditory condition is tinnitus.
 40. The system of claim20, wherein the auditory condition is hyperacusis.
 41. A non-transitorycomputer-readable storage medium having stored thereon a set ofinstructions, executable by a processor, for treating an auditorycondition in a subject, the instructions comprising: instructions forgenerating an audible stimulation signal having a first firing point andfirst firing period, stimulus onset, and/or duration; instructions forgenerating a somatosensory stimulation signal to stimulate asomatosensory system of a subject, the somatosensory stimulation signalhaving a second firing point and second firing period, stimulus onset,and/or duration; and instructions for establishing a timing order andtiming difference between the first firing point and the second firingpoint to reduce auditory condition, wherein the first firing period andthe second firing period are to be maintained asynchronously to reducethe auditory condition so that the first firing period does not overlapthe second firing period; and instructions for controlling asomatosensory signal generator to apply the somatosensory stimulationsignal to the somatosensory system of the subject, and instructions forcontrolling an audible signal generator to apply the audible stimulationsignal to an auditory system of the subject for reducing tinnitus in thesubject.
 42. The non-transitory computer-readable storage medium ofclaim 41, wherein the auditory condition is the tinnitus.
 43. Thenon-transitory computer-readable storage medium of claim 41, wherein theauditory condition is hyperacusis.
 44. The non-transitorycomputer-readable storage medium of claim 41, the instructions furthercomprising: instructions for determining optimal parameter values for anaudible stimulation signal and a somatosensory stimulation signal toalter firing rates for neurons in the auditory and non-auditory pathwaysinvolved in the auditory condition.
 45. The non-transitorycomputer-readable storage medium of claim 41, the instructions furthercomprising: instructions for increasing firing rates for the neurons inthe auditory and non-auditory pathways involved in the auditorycondition.
 46. The non-transitory computer-readable storage medium ofclaim 41, the instructions further comprising: instructions fordecreasing firing rates for the neurons in the auditory and non-auditorypathways involved in the auditory condition.